Semaglutide Plus Cagrilintide Reduced Blood Sugar, Weight in T2D

SAN DIEGO -- Treatment with semaglutide 2.4 mg co-administered with the investigational long-acting amylin analogue cagrilintide (known together as CagriSema) led to improvements in glycemic control and reductions in body weight in patients with type 2 diabetes, a randomized phase II trial showed.

At 32 weeks, patients treated with once-weekly injections of CagriSema had an HbA1c reduction of 2.2% compared with reductions of 1.8% with semaglutide alone and 0.9% with cagrilintide alone, reported Juan Frías, MD, of Velocity Clinical Research in Los Angeles, during the American Diabetes Association (ADA) Scientific Sessions.

The mean change in HbA1c was greater with CagriSema versus cagrilintide (P<0.0001), but not versus semaglutide (P=0.075), according to the study's results, which were also published in The Lancet.

"Almost 90% of the CagriSema patients achieved an A1c of less than 7%, and three-quarters achieved an A1c of less or equal to 6.5%," Frías noted in his presentation, adding that there were also "clinically relevant improvements" in blood pressure, lipids, and high-sensitivity C-reactive protein at week 32.

In addition, CagriSema outperformed both treatments alone for the secondary endpoint of change in body weight, with patients receiving CagriSema losing a mean of 15.6% of body weight versus 5.1% with semaglutide and 8.1% with cagrilintide (P<0.0001 for both). The greatest decrease in mean glucose measured by continuous glucose monitoring from baseline to 32 weeks was also observed in the CagriSema group, with a mean drop of 3.6 mmol/L compared with drops of 2.4 and 1.3 mmol/L, respectively.

Furthermore, the mean change in fasting plasma glucose from baseline to week 32 was greater with CagriSema (-3.3 mmol/L) versus cagrilintide (-1.7 mmol/L; P=0.0010) but not versus semaglutide (-2.5 mmol/L; P=0.10). Time in range (defined as 3.9-10.0 mmol/L) was 45.9%, 32.6%, and 56.9% at baseline and 88.9%, 76.2%, and 71.7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively.

In an accompanying comment, Caroline Apovian, MD, and Marie McDonnell, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, pointed out that "CagriSema is the next in a series of gut hormone analogues with the potential to herald a new era in treating obesity and preventing diabesity."

"Both [drugs] effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain," Apovian and McDonnell wrote. "Interestingly, given the substantial difference in effect size between the combination drug and each component alone, we can conclude that there is a synergistic effect for both glycemic control and weight loss."

There are three clinical trials underway to study weight loss with CagriSema, and Frías and team noted that the efficacy and safety profiles from this trial warrant further investigation into the drug specifically for patients with type 2 diabetes.

This double-blind study was conducted from August 2021 to July 2022 at 17 sites in the U.S. The 92 included patients (mean age 58, 64% men, 78% white, 16% Black) were taking daily metformin with or without an SGLT2 inhibitor, had a body mass index (BMI) of 27 or higher (average BMI 35.5), and a baseline HbA1c between 7.5% and 10%.

Participants were randomized 1:1:1 to once-weekly co-administered injections of semaglutide and cagrilintide, once-weekly co-administered injections of semaglutide and placebo, and once-weekly co-administered injections of cagrilintide and placebo. Dosage remained consistent across groups, and was escalated every 4 weeks to the final 2.4-mg dose after 16 weeks, followed by 16 weeks of maintenance and a 5-week follow-up period.

Of note, more patients taking CagriSema experienced gastrointestinal events than those taking semaglutide or cagrilintide (58% vs 32% and 33%), with nausea, constipation, and diarrhea most commonly reported.

Frías and colleagues explained that the adverse events were all of mild and moderate severity, and happened "mostly during dose escalation." The overall safety profile of the drug is consistent with other GLP-1 receptor agonists and amylin analogues, Frías said.

Although the average diabetes duration among all participants was 8.7 years, it varied among the study groups, with an average of 6.4 years in the CagriSema group, 9.2 years in the semaglutide group, and 10.7 years in the cagrilintide group.

Apovian and McDonnell noted that the shorter diabetes duration in the CagriSema group, "could have potentially yielded a more favorable glycemic outcome in [this] group due to preserved β-cell function."

Frías and team said the study's small sample size and relatively short duration were limitations. The estimated reduction in body weight with semaglutide at 32 weeks was also lower than that shown in previous studies.